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Inter-nucleosomal communication between histone modifications for nucleosome phasing.

ABSTRACT: Combinatorial effects of epigenetic modifications on transcription activity have been proposed as "histone codes". However, it is unclear whether there also exist inter-nucleosomal communications among epigenetic modifications at single nucleosome level, and if so, what functional roles they play. Meanwhile, how clear nucleosome patterns, such as nucleosome phasing and depletion, are formed at functional regions remains an intriguing enigma. To address these questions, we developed a Bayesian network model for interactions among different histone modifications across neighboring nucleosomes, based on the framework of dynamic Bayesian network (DBN). From this model, we found that robust inter-nucleosomal interactions exist around transcription start site (TSS), transcription termination sites (TTS) or around CTCF binding sites; and these inter-nucleosomal interactions are often involved in transcription regulation. In addition to these general principles, DBN also uncovered a novel specific epigenetic interaction between H2A.Z and H4K20me1 on neighboring nucleosomes, involved in nucleosome free region (NFR) and nucleosome phasing establishment or maintenance. The level of negative correlation between neighboring H2A.Z and H4K20me1 strongly correlate with the size of NFR and the strength of nucleosome phasing around TSS. Our study revealed inter-nucleosomal communications as important players in signal propagation, chromatin remodeling and transcription regulation.

SUBMITTER: Chen W

PROVIDER: S-EPMC6126837 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Inter-nucleosomal communication between histone modifications for nucleosome phasing.

Chen Weizhong W Liu Yi Y Zhu Shanshan S Chen Guoyu G Han Jing-Dong J JJ

PLoS computational biology 20180906 9

Combinatorial effects of epigenetic modifications on transcription activity have been proposed as "histone codes". However, it is unclear whether there also exist inter-nucleosomal communications among epigenetic modifications at single nucleosome level, and if so, what functional roles they play. Meanwhile, how clear nucleosome patterns, such as nucleosome phasing and depletion, are formed at functional regions remains an intriguing enigma. To address these questions, we developed a Bayesian ne ...[more]

PMID: 30188887

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Project description:BACKGROUND:Controlled modulation of nucleosomal DNA accessibility via post-translational modifications (PTM) is a critical component to many cellular functions. Charge-altering PTMs in the globular histone core-including acetylation, phosphorylation, crotonylation, propionylation, butyrylation, formylation, and citrullination-can alter the strong electrostatic interactions between the oppositely charged nucleosomal DNA and the histone proteins and thus modulate accessibility of the nucleosomal DNA, affecting processes that depend on access to the genetic information, such as transcription. However, direct experimental investigation of the effects of these PTMs is very difficult. Theoretical models can rationalize existing observations, suggest working hypotheses for future experiments, and provide a unifying framework for connecting PTMs with the observed effects. RESULTS:A physics-based framework is proposed that predicts the effect of charge-altering PTMs in the histone core, quantitatively for several types of lysine charge-neutralizing PTMs including acetylation, and qualitatively for all phosphorylations, on the nucleosome stability and subsequent changes in DNA accessibility, making a connection to resulting biological phenotypes. The framework takes into account multiple partially assembled states of the nucleosome at the atomic resolution. The framework is validated against experimentally known nucleosome stability changes due to the acetylation of specific lysines, and their effect on transcription. The predicted effect of charge-altering PTMs on DNA accessibility can vary dramatically, from virtually none to a strong, region-dependent increase in accessibility of the nucleosomal DNA; in some cases, e.g., H4K44, H2AK75, and H2BK57, the effect is significantly stronger than that of the extensively studied acetylation sites such H3K56, H3K115 or H3K122. Proximity to the DNA is suggestive of the strength of the PTM effect, but there are many exceptions. For the vast majority of charge-altering PTMs, the predicted increase in the DNA accessibility should be large enough to result in a measurable modulation of transcription. However, a few possible PTMs, such as acetylation of H4K77, counterintuitively decrease the DNA accessibility, suggestive of the repressed chromatin. A structural explanation for the phenomenon is provided. For the majority of charge-altering PTMs, the effect on DNA accessibility is simply additive (noncooperative), but there are exceptions, e.g., simultaneous acetylation of H4K79 and H3K122, where the combined effect is amplified. The amplification is a direct consequence of the nucleosome-DNA complex having more than two structural states. The effect of individual PTMs is classified based on changes in the accessibility of various regions throughout the nucleosomal DNA. The PTM's resulting imprint on the DNA accessibility, "PTMprint," is used to predict effects of many yet unexplored PTMs. For example, acetylation of H4K44 yields a PTMprint similar to the PTMprint of H3K56, and thus acetylation of H4K44 is predicted to lead to a wide range of strong biological effects. CONCLUSION:Charge-altering post-translational modifications in the relatively unexplored globular histone core may provide a precision mechanism for controlling accessibility to the nucleosomal DNA.

Dataset Information

Inter-nucleosomal communication between histone modifications for nucleosome phasing.

Publications

Inter-nucleosomal communication between histone modifications for nucleosome phasing.

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